title: Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K.
abstract: PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Pecchi
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Ni
authors.forename: Wooseok
authors.initials: W
authors.lastname: Han
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.forename: Matthew
authors.initials: M
authors.lastname: Burger
authors.forename: Hanne
authors.initials: H
authors.lastname: Merritt
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.forename: John
authors.initials: J
authors.lastname: Chan
authors.forename: Susan
authors.initials: S
authors.lastname: Kaufman
authors.forename: Mark S
authors.initials: MS
authors.lastname: Knapp
authors.forename: Johanna
authors.initials: J
authors.lastname: Janssen
authors.forename: Kay
authors.initials: K
authors.lastname: Huh
authors.forename: Charles F
authors.initials: CF
authors.lastname: Voliva
mesh_terms: D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D001391:Azo Compounds; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D007094:Imides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; C005465:benzothiazole
keywords: Cancer; Imidazopyridine; Lipid kinase; PI3 kinase inhibitor; Scaffold morphing; Structure-guided drug design